Preparation of N-protected-3-pyrrolidine-lactam substituted phosphonium salts

ABSTRACT

A process for producing the compound (1′benzyl-2-oxo-[1,3′]-(R)-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium bromide which is an intermediate for antibacterial vinylpyrrolidinone-cephalosporin derivatives.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of Ser. No. 10/916,954filed Aug. 12, 2004 now U.S. Pat. No. 7,262,307 which in turn is adivisional of Ser. No. 10/344,903 filed Feb. 14, 2003, now U.S. Pat. No.6,828,442 issued Dec. 7, 2004.

The invention relates to a new process for the preparation of(1′-tert-butoxycarbonyl-2-oxo-[1,3′]-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphoniumhalogenide compounds of formula I

-   -   wherein * signifies an asymmetric center with an (R) or (S)        configuration and X represents chlorine, bromine or iodine.

The compounds of formula I are known from EP-A 0 849 269 and can beobtained through multiple-step synthesis of the correspondingallyloxycarbonyl (ALLOC) protected [1,3′]bipyrrolidinyl-2-oxo derivativeby removal of the allyloxycarbonyl protecting group and protectionreaction with a tert-butoxycarbonyl moiety to yield tert-butoxycarbonyl(t-BOC) protected [1,3′]bipyrrolidinyl-2-oxo compounds of formula I.

It has now been found that the compounds of formula I can bemanufactured in an improved and shortened way by the process of thepresent invention. The new process for the preparation of(1′-tert-butoxycarbonyl-2-oxo-[1,3′]-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphoniumhalogenide compounds of formula I

-   -   wherein * signifies an asymmetric center with an (R) or (S)        configuration and X represents chlorine, bromine or iodine;        comprises

-   step 1) coupling N-benzyl-3-pyrrolidinamine of formula II

-   -   wherein * is as defined above        with a compound of formula X(CH₂)₂CH(X)COX    -   wherein X is independently of each other chlorine, bromine or        iodine; and        subsequent cyclization in the presence of a base to obtain a        compound of formula III

-   -   wherein * and X are as defined above;

-   step 2) reacting the compound of formula III with triphenylphosphine    to obtain the phosphonium salt of formula IV

-   -   wherein * and X are as defined above; and

-   step 3) reacting the phosphonium salt of formula IV with    di-tert.-butyl-dicarbonate under hydrogenation conditions to obtain    the compounds of formula I.

Surprisingly, it has been found that the N-benzyl-3-pyrrolidinamine offormula II undergoes the reaction sequence described above to yield thecompounds of formula I, despite the expected instability of intermediateIII. The corresponding t-Boc and Alloc protected derivatives of startingmaterial of formula II are not available through the described process

In the structural formulae of the compounds given throughout thisapplication, a wedged bond (

) indicates a substituent which is above the plane of the paper.

In the structural formulae of the compounds given throughout thisapplication, a dotted bond (

) indicates a substituent which is below the plane of the paper.

The compounds of the present process invention exhibit stereoisomerismand can be any stereoisomer. The compounds of the present processinvention having one asymmetric carbon atom may be obtained as racemicmixtures of stereoisomers which can be resolved, at the appropriatesteps in the process of this invention by methods well known in the artto obtain a given stereoisomer or pure enantiomer having a desiredstereoconfiguration. Alternatively, the desired isomers may be directlysynthesized by methods known in the art.

The asymmetric carbon atom in the compound of the present invention isdenoted as “*”. The stereoconfiguration of the asymmetric carbon atomdenoted as “*” can be designated according to the particularstereoisomer it represents. Compounds of the present invention includethose compounds wherein the carbon atom denoted as “*” have the S, R orR,S-configuration, preferably the R-configuration.

The term halogen stands for chlorine, bromine and iodine, more preferredchlorine or bromine, most preferred halogen is bromine.

The compounds of the present invention are prepared as shown in thereaction scheme 1.

wherein * and X are as defined above.

In the 1^(st) step of the reaction the compound of formula II is coupledwith 1-4 equivalents, preferably 1-2 equivalents of X(CH₂)₂CH(X)COXwherein X is independently of each other chlorine or bromine or iodine,preferably bromine (preparation see below) in the presence of bases suchas Na₃PO₄, K₂CO₃, Na₂CO₃, KOH or NaOH, preferably Na₃PO₄ and anappropriate solvent. Appropriate solvents are polar aprotic solventssuch as acetonitrile (CH₃CN), dimethylsulfoxide (DMSO),dimethylacetamide or N,N-dimethylformamide (DMF), preferably CH₃CN. Thereaction is carried out at a reaction temperature between about −20° C.and about 30° C., preferably at a reaction temperature between about−10° C. and about 10° C. Subsequently, a cyclization reaction is carriedout with the intermediate coupling product to obtain compounds offormula III. The cyclization reaction is carried out in the presence of1-3 equivalents, preferably 2-2.5 equivalents of a base, such as K₂CO₃,Na₂CO₃, KOH or NaOH, preferably NaOH in aqueous solution, at a reactiontemperature between about −10° C. and about 50° C., preferably betweenabout 10° C. and about 30° C.

Compounds of formula X(CH₂)₂CH(X)COX wherein X is independently of eachother chlorine or bromine or iodine are commercially available or aresynthesized according to methods known from textbooks. For example thecompound of formula X(CH₂)₂CH(X)COX wherein X is chlorine is preparedaccording to Mathew, K. K. et al. Indian J. Chem., Sect. B (1981),20B(4), 340-2. The compound of formula X(CH₂)₂CH(X)COX wherein X isbromine is prepared according to Marinelli, E. R. et al. Tetrahedron(1996), 52(34), 11177-11214. The compound of formula X(CH₂)₂CH(X)COXwherein X is iodine can be obtained by reacting the tribromide (X═Br)with NaI in CH₃CN.

In a preferred embodiment of the invention the compound of formula IIIa

is formed according to the above described 1^(st) step of the reaction.The compound of formula IIIa is new and therefore part of the presentinvention.

In the 2^(nd) step of the process the compound of formula III is reactedwith 1-5 equivalents, preferably 2-4 equivalents of triphenylphosphineto obtain the phosphonium salt of formula IV. The reaction is carriedout in an aromatic solvent such as toluene, o-xylene, m-xylene, p-xyleneor benzene, preferably toluene at a reaction temperature between about20° C. and about 180° C., preferably between about 80° C. and about 140°C.

In a preferred embodiment of the invention the compound of formula IVa

is formed according to the above described 2^(nd) step of the reaction.The compound of formula IVa is new and therefore part of the presentinvention.

In the 3^(rd) step of the process the phosphonium salt of formula IV isreacted with 1-5 equivalents, preferably 2-4 equivalents ofdi-tert.-butyl-dicarbonate (commercially available from Fluka) underhydrogenation conditions in the presence of a catalyst such as Pd/C(commercially available from Degussa) preferably with 10% Pd onactivated carbon, to obtain compounds of formula I. The reaction iscarried out in an alcoholic solvent such as methanol, ethanol orisopropanol, preferably in methanol at a reaction temperature betweenabout 10° C. and about 100° C., preferably between about 40° C. andabout 80° C.

In a preferred embodiment of the invention steps 1-3 are carried out forcompounds wherein * signifies an asymmetric center with (R)configuration and X is chlorine or bromine, preferably bromine.

Compounds of formula II, used as starting material in the presentprocess is prepared according reaction steps a→b→c as shown in reactionscheme 2. The preparation of the compound of formula II is also part ofthe present invention.

-   -   wherein R¹ is alkyl, R² is an amino protecting group and * is as        defined above.

The terms which have already been mentioned and will be mentioned in thedescription of the invention are defined as follows:

The term “alkyl” as used herein denotes an optionally substitutedstraight or branched chain hydrocarbon residue containing 1 to 12 carbonatoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl and its isomers.

Alkyl in R¹ is preferably unsubstituted straight or branched chainhydrocarbon residue containing 1 to 4 carbon atoms, more preferredmethyl or ethyl, and most preferred methyl.

The term “amino protecting group” as used herein refers to groups suchas those employed in peptide chemistry, such as an allyloxycarbonylgroup (ALLOC), a lower alkoxycarbonyl group such as tert-butoxycarbonyl(t-BOC) and the like, a substituted lower alkoxycarbonyl group such astrichloroethoxycarbonyl, an optionally substituted aryloxycarbonyl groupfor example p-nitrobenzyloxycarbonyl or benzyloxycarbonyl (Z), anarylalkyl group such as triphenylmethyl (trityl), benzhydryl or benzyl,an alkanoyl group such as formyl, acetyl or benzoyl, a halogen-alkanoylgroup such as trifluoroacetyl, or a silyl protective group such as thetert-butyldimethylsilyl group.

Preferred amino protecting groups are benzyloxycarbonyl,tert-butoxycarbonyl or allyloxycarbonyl.

An especially preferred amino protecting for R² is the benzyloxycarbonylgroup.

The term “lower alkoxy” signifies an alkyl group as defined above whichis bonded via an oxygen atom. Examples are methoxy, ethoxy, propyloxy,butoxy, tert. butoxy and the like.

The term “aryl” as used herein denotes an optionally substituted phenylgroup (Ph) in which one or more aryl hydrogen atoms can be substitutedby one or more phenyl groups, alkyl groups, lower alkoxy groups,halogenated alkyl groups, halogen atoms or nitro. Examples are phenyl,o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl,p-methoxyphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl,p-trifluoromethylphenyl, o-trichloromethylphenyl,m-trichloromethylphenyl, p-trichloromethylphenyl, p-fluorophenylp-chlorophenyl, p-bromophenyl, p-nitrophenyl.

The term “aryloxy” signifies an aryl group as defined above which isbonded via an oxygen atom. Examples are phenyloxy, benzyloxy and thelike.

The term “lower alkoxycarbonyl” denotes lower alkoxy residues asdefined, attached to a carbonyl group (—C(═O)). Examples aremethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyland the like.

The term “aryloxycarbonyl” denotes aryloxy residues as defined, attachedto carbonyl group (—C(═O)). Examples are phenyloxycarbonyl andbenzyloxycarbonyl.

The term “arylalkyl” as used herein denotes a hydrocarbon group in whichone or more alkyl hydrogen atoms are substituted by an aryl group asdefined. Examples are trityl, benzhydryl or benzyl.

The term “hydroxy protecting group” as used herein denotes an alkylgroup, a cycloalkyl group or an arylalkyl group. A preferred hydroxyprotecting group is an arylalkyl group, especially preferred is atriphenylmethyl (trityl) group.

The term “carboxylic acid protecting group” includes protecting groupswhich are usually used to replace a proton of the carboxyl group.Examples of such groups are described in Green T. Protective Groups inOrganic Synthesis, Chapter 5, John Wiley and Sons, Inc. (1981), pp.152-192. Examples of such protecting groups are: benzhydryl,tert.-butyl, p-nitrobenzyl, p-methoxybenzyl, methoxymethyl and the like.Benzhydryl is a preferred carboxylic acid protecting group.

The term “cycloalkyl” as used herein denotes a 3-6 membered saturatedcarbocyclic moiety, e.g. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, preferably cyclohexyl.

In step (a) of the reaction the asparagine derivatives of formula V(preparation see below) is treated with 0.5-2.0 equivalents, preferably1.0-1.5 equivalents of a base such as NaH, NaOH or KOH, preferably withNaH, in an appropriate solvent to obtain the cyclic intermediate offormula A

-   -   wherein * and R² are as defined above.

Appropriate solvents for the cyclization reaction are ethers such astetrahydrofuran, diethyl ether, dioxane or a mixture of the mentionedsolvents, preferably tetrahydrofuran. Then, in a preferred embodiment ofthe invention, the intermediate of formula A is reacted withcommercially available benzyl bromide in the presence of an appropriatesolvent to obtain the 3-amino protected benzyl-2,5-dioxo-pyrrolidine offormula VI. Appropriate solvents are polar aprotic solvents such asdimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide(DMF), preferably DMF. The reaction is carried out at a temperaturebetween about 0° C. and about 50° C., preferably between about 10° C.and about 40° C.

In another embodiment of the invention the intermediate of formula A isreacted with commercially available p-methoxybenzylbromide,3,4-dimethoxybenzylbromide, trityl chloride, methoxy methyl chloride orallyl bromide under above-described reaction conditions or alternativelyaccording to methods known from textbooks on organic chemistry (e.g. J.March (1992), “Advanced Organic Chemistry: Reactions, Mechanisms, andStructure”, 4^(th) ed. John Wiley & Sons) to obtain the corresponding1-N-substituted 3-amino protected-2,5-dioxo-pyrrolidine of formula VI.

The reaction of step (a) can optionally be carried via a two stepprocedure. First, the asparagine derivatives of formula V is treatedwith 0.5-2.0 equivalents, preferably 1.0-1.5 equivalents of a base suchas NaH, NaOH or KOH, preferably with NaH in an appropriate solvent toobtain the cyclic compound of formula A. Appropriate solvents for thisfirst step are ethers such as tetrahydrofuran, diethyl ether, dioxane ora mixture of the mentioned solvents, preferably tetrahydrofuran. Thereaction is carried out at a temperature between about −10° C. and about30° C., preferably starting at 0° C.; during the reaction thetemperature is increased to room temperature. After the reaction, thereaction mixture is acidified to a pH in the range between 3.0 and 5.0,preferably between 3.5 and 4.5, and then the organic solvent isevaporated. Secondly, the compound of formula A is treated with a basesuch as NaH, NaOH or KOH, preferably with NaH in ethers such astetrahydrofuran, diethyl ether, dioxane or a mixture of the mentionedsolvents, preferably in tetrahydrofuran.

Then, in a preferred embodiment of the invention, the mixture is reactedwith commercially available benzyl bromide in the presence of anappropriate solvent to obtain the 3-amino protectedbenzyl-2,5-dioxo-pyrrolidine of formula VI. Appropriate solvents for thereaction are polar aprotic solvents such as dimethylsulfoxide (DMSO),dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF. Thereaction is carried out at a temperature between about −10° C. and about30° C., preferably starting at 0° C.; during the reaction the reactiontemperature is increased to room temperature. After the reaction, theproduct is worked-up in a manner known in the art for example quenchedwith H₂O and extracted with an aromatic solvent such as toluene,o-xylene, m-xylene, p-xylene or benzene preferably toluene, dried overanhydrous magnesium sulfate, sodium sulfate, calcium chloride,preferably magnesium sulfate and finally the organic solvent isevaporated.

In another embodiment of the invention the mixture is reacted withcommercially available p-methoxybenzylbromide,3,4-dimethoxybenzylbromide, trityl chloride, methoxy methyl chloride orallyl bromide under above-described reaction conditions or alternativelyaccording to methods known from textbooks on organic chemistry (e.g. J.March (1992), “Advanced Organic Chemistry: Reactions, Mechanisms, andStructure” 4^(th) ed. John Wiley & Sons) to obtain the corresponding1-N-substituted 3-amino protected-2,5-dioxo-pyrrolidine of formula VI.

Asparagine derivatives of formula V are commercially available or can besynthesized according to methods known from textbooks on organicchemistry (e.g. J. March (1992), “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure”, 4^(th) ed. John Wiley & Sons) for examplestarting with D- or L-asparagine (Fluka) protection of the free aminofunction and subsequent esterification to obtain the correspondingasparagine derivatives of formula V.

The advantage of carrying out the reaction of step (a) via a two stepprocedure is that the compounds of formula VI are obtained in higheryield. The two step procedure is also a part of the present invention.

In step (b) of the process the amino protecting group (R²) of thecompounds of formula VI is removed under condition described below.Preferred amino protecting groups for R² are benzyloxycarbonyl,tert-butoxycarbonyl or allyloxycarbonyl, most preferredbenzyloxycarbonyl. The benzyloxycarbonyl amino protecting group is forexample removed under hydrogenation conditions in the presence of acatalyst such as Pd/C (commercially available from Degussa) preferablywith 10% Pd on activated carbon. The deprotection reactions are carriedout in the presence of acetic acid, trifluoroacetic acid, ethanolic HCl,methanesulphonic acid or fluorosuphonic acid to obtain the correspondingamino salt of formula VII which is more stable than the free base andtherefore can be stored without degradation. In a preferred embodimentacetic acid is used to prepare the acetic acid salt of formula VII. Thereaction is carried out at a temperature between about 10° C. and about50° C., preferably between about 20° C. and about 40° C.

Depending on the amino protecting groups the deprotection is carried outas follows:

The amino protecting groups may be cleaved off by acid hydrolysis (e.g.the tert-butoxycarbonyl or trityl group), e.g. aqueous formic acid,trifluoroacetic acid or by basic hydrolysis (e.g. the trifluoroacetylgroup). Further protecting groups may be cleaved off by hydrazinolysis(e.g. the phthalimido group). The allyloxycarbonyl group may be cleavedoff by Pd catalysed transfer to nucleophiles. The chloroacetyl,bromoacetyl and iodoacetyl groups are cleaved off by treatment withthiourea.

Amino protecting groups which are cleavable by acid hydrolysis arepreferably removed with the aid of a lower alkanecarboxylic acid whichmay be halogenated. In particular, formic acid or trifluoroacetic acidis used. The reaction is carried out in the acid or in the presence of aco-solvent such as a halogenated lower alkane, e.g. methylene chloride.The acid hydrolysis is generally carried out at room temperature,although it can be carried out at a slightly higher or slightly lowertemperature (e.g. a temperature in the range of about −30° C. to 40°C.). Protecting groups which are cleavable under basic conditions aregenerally hydrolyzed with dilute aqueous caustic alkali at 0° C. to 30°C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can becleaved off using thiourea in acidic, neutral or alkaline medium atabout 0° C. to 30° C.

In step (c) of the process the amino salt compound of formula VII istreated with a base such as NaOH, KOH, Na₂CO₃ or K₂CO₃ preferably withNaOH in aqueous solution to adjust the pH in the ranges from 7.0 to 9.0,preferably in the range from 7.5 to 8.5 in the presence of a halogenatedhydrocarbon such as monochloromethane or dichloromethane, preferablydichloromethane, to remove the acid and to obtain the intermediate acidfree compound of formula VII. The intermediate is then worked-up byextraction with a halogenated hydrocarbon such as monochloromethane ordichloromethane, preferably dichloromethane and then the organic solventis evaporated. Subsequently, the acid free derivative of formula VII isreduced with a reducing agent such as Vitride®, NaBH₄, LiBH₄, LiAlH₄,BH₃.THF, preferably with Vitride®, to obtain the amino pyrrolidine offormula II. The reducing agents are commercially available from Aldrichor Fluka. The reaction is carried out in an aromatic solvent such astoluene, o-xylene, m-xylene, p-xylene or benzene, preferably withtoluene at a reaction temperature between about −10° C. and about 100°C., preferably starting at 0° C.; during the reaction the temperature isincreased to 80° C. Then, the mixture is cooled to a temperature betweenabout −20° C. and about 20° C., preferably to a temperature betweenabout −10° C. and about 10° C. and treated with a base such as sodiumhydroxide in aqueous solution.

In a preferred embodiment of the process steps a-c are carried out forcompounds wherein * signifies an asymmetric center with (R)configuration and R¹ is methyl or ethyl, preferably methyl and R² isbenzyloxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl, preferablybenzyloxycarbonyl and X is chlorine or bromine, preferably bromine.

The compounds of formula I-VII are important building blocks for theproduction of useful products in the chemical and pharmaceuticalindustry. In particular they are useful for the production ofantibacterial substances for example vinylpyrrolidinone-cephalosporinderivatives as described in EP-A 0 849 269. Preferably compounds offormula I-VII are useful for the preparation of compounds of formulaVIII

-   -   wherein R³ is a hydroxy protecting group, R⁴ is a carboxylic        acid protecting group, * is as defined above and R⁵ is an amino        protecting group preferably a tert-butoxycarbonyl group or a        group of formula B

-   -   wherein R⁶ is preferably an unsubstituted straight chain or        branched alkyl group containing 1 to 4 carbon atoms, more        preferred methyl, ethyl or isopropyl and most preferred methyl.

The preparation of compounds of formula VIII is described in EP-A 0 849269.

In the following examples the abbreviations used have the followingsignification's.

ISP-MS ion spray positive mass spectroscopy EI-MS electron impact massspectroscopy GC gas chromatography SFC super critical fluidchromatography NMR nuclear magnetic resonance spectroscopy IR infraredspectroscopy TLC thin layer chromatography HPLC high performance liquidchromatography HV high vacuum FID flame ionization detector THFtetrahydrofurane DMF N,N-dimethylformamide DMSO dimethylsulfoxide TBMEtert.-butyl methyl ether TFA trifluoracetic acid TBAHStetrabutylammonium hydrogen sulfate min minute(s) h hour(s) rt roomtemperature

EXAMPLE 1 Preparation of(R)-(1-benzyl-2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester

1.1 (via one step): A suspension of 1.12 g of 60% NaH in 75 ml of THF istreated with 7.50 g of Z-(D)-asparagine methyl ester (99.9% (R)-isomer)(synthesized according to J. Liq. Chromatogr. (1994), 17(13), 2759 orfor example starting with D-asparagine (Fluka) and protecting the freeamino function with a benzyloxycarbonyl group and subsequentesterification to the corresponding methyl ester asparagine derivativeof formula I; the reactions are carried out according to textbook oforganic chemistry e.g. J. March (1992), “Advanced Organic Chemistry:Reactions, Mechanisms, and Structure”, 4^(th) ed. John Wiley & Sons)over 5 min at rt. After 20 min, 3.57 ml of benzyl bromide (commerciallyavailable from Fluka) was added, followed by 120 ml of DMF. After 3 h,the conversion was completed (indicated by HPLC). The reaction wasquenched with 150 ml H₂O and extracted three times with 120 ml oftoluene. The organic layer was washed with H₂O, dried over MgSO₄,filtered and the filtrate was evaporated to dryness. The residue wastriturated in 100 ml of TBME, the resultant suspension filtered anddried (35° C./10 mbar) to give 8.13 g (90%) of(R)-(1-benzyl-2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester aswhite crystals: m.p. 143.3-144.5° C. Optically pure material could beobtained from crystallization from CH₂Cl₂/n-hexane, 72% recovery; m.p.145.9-146.7° C.; 99.9% (R)-isomer.

1.2.1 (via two steps; 1^(st) step): A suspension of 856 mg of 60% NaH in50 ml THF at 0° C. was treated with 5.0 g of Z-(D)-asparagine methylester 3 (99.9% (R)-isomer) and stirred at rt for 90 min whereupon TLCindicated complete consumption of the starting material. The reactionmixture was acidified to pH 4 with 6.0 ml of AcOH and the THF distilledaway. The remaining aqueous layer was extracted three times with 20 mlof TBME and the combined organic phases washed with 20 ml of brine,dried over MgSO₄ and concentrated to give 4.66 g of a white sticky solid(105% contains ˜5% w/w AcOH) of (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamicacid benzyl ester as a white sticky solid which was used directly forthe second step (example 1.2.2) below. Digestion in EtOAc/n-hexane gave3.47 g (75%) of (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzylester as white crystals, m.p. 117.2-117.8° C.

1.2.2 (via two steps; 2^(nd) step): A suspension of 48.4 mg of 60% NaHin 3 ml of THF was treated with 300 mg of(R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester at 0° C.followed by 161.3 μL of benzyl bromide. After 30 min the resultingprecipitate was warmed to rt and treated with 3 ml of DMF to give after15 min a solution which was stirred for 16 h at rt then quenched with 60ml of H₂O and extracted with 40 ml of toluene. The combined organiclayers were dried over MgSO₄ and concentrated to give 409 mg (74%) ofthe (R)-(2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester as whitecrystals; m.p. 145.1-145.5° C. Overall yield for the two step process:78%.

EXAMPLE 2 Preparation of 3-(R)-amino-1-benzyl-pyrrolidin-2,5-dioneacetic acid (1:2)

A solution of 7.80 g of(R)-(1-benzyl-2,5-dioxo-pyrrolidin-3-yl)-carbamic acid benzyl ester (93%(R)-isomer) in 160 ml of acetic acid was treated with 0.78 g of 10% Pd/C(commercially available from Degussa; 1835) and hydrogenated at 30° C.for 20 min whereupon TLC and HPLC indicated completion of the reaction.The reaction mixture was filtered, evaporated and the residuecrystallized from EtOAc and n-hexane to give 5.80 g (78%) of3-(R)-amino-1-benzyl-pyrrolidin-2,5-dione acetic acid (1:2) as whitecrystals; HPLC (100%): HP 1050, nucleosil 100-5 C18 column, CH₃CN, H₂O,TFA system buffered with TBAHS; GC (99.8% as free amine): J and W, DB-1,15 m×0.32 mm, carrier gas He, program: 50-320° C. (5° C./min); injectortemp. 250° C.; FID: 320° C.; 91% (R)-isomer, analyzed as thecorresponding trifluoroacetamide by GC (BGB-177): 15 m×0.25 mm, carriergas: He; program: 150° C.-200° C. at 1° C./min; injector temp. 210° C.;FID: 220° C.; NMR (CDCl₃, 400 MHz; 1.6 eq AcOH) 7.32 (m, 5H, H-ar), 5.64(bs, 4H, NH), 4.65 (s, 2H, PhCH₂O, 3.92 (dd, J=5.4 and 7.8, 1H, NCH),3.05 (dd, J=7.8 and 18, COCH₂, 1H), 2.50 (dd, J=18 and 5.4, COCH₂, 1H),2.08 (s, 2×CH₃CO₂, 6H).

EXAMPLE 3 Preparation of (R)-1-(phenylmethyl)-3-pyrrolidinamine

A solution of 10.87 g of 3-(R)-amino-1-benzyl-pyrrolidine-2,5-dioneacetic acid (1:2) in 100 ml of H₂O was treated with 100 ml of CH₂Cl₂followed by 67.60 ml of 1 N NaOH at rt to pH 8.0. After saturation withNaCl, the mixture was extracted seven times with 100 ml of CH₂Cl₂, driedover MgSO₄ and evaporated at 35° C./10 mbar to give 6.32 g (97%) of theNMR clean free base as a pale yellow solid. NMR (CDCl₃, 250 MHz): 7.30(m, 5H, H-ar), 4.64 (s, 2H, PhCH₂), 3.88 (dd, J=5 and 7.5, 1H, NCH),3.04 (dd, J=7.5 and 17.5, 1H, COCH₂), 2.43 (dd, J=5 and 17.5, 1H,COCH₂).

5.90 g of this yellow oil was treated at 0° C. over 20 min with 33 ml ofa 3.5 M solution of Vitride® in toluene and the resultant yellow-orangesolution was warmed to 80° C. for 30 min (MS indicated completion of thereaction), cooled to 0° C. and treated with 80 ml of 1 N NaOH solution.The phases were separated and the aqueous phase extracted with twofurther portions of 15 ml toluene. The combined organic phases werewashed with 76 ml 1N NaOH, 70 ml brine, dried and evaporated to give4.42 g (87%) of (R)-1-(phenylmethyl)-3-pyrrolidinamine, as a light brownoil. GC: (97%, J and W, DB-1, conditions as described for example 2; 93%(R)-isomer, analyzed as the corresponding trifluoroacetamide by GC:(BGB-177), conditions as described for example 2; MS (Ion Spray): 177.1(M+H⁺); 1H-NMR (CDCl₃, 250 MHz): 7.28 (m, 5H, H-ar), 3.63 and 3.56 (2×d,J=12.5, 2H, PhCH₂N), 2.69 (m, 2H, NCH ₂CHNH₂ and NCH ₂CH₂CHNH₂), 2.44(m, 1H, NCH ₂CH₂CHNH₂), 2.24 (dd, J=4.5 and 9.5, 1H, NCH ₂CHNH₂), 2.15(m, 1H, NCH₂CH ₂CHNH₂), 1.45 (bm, 3H, NH₂ and NCH₂CH ₂CHNH₂); IR (Film):(NH) 3357 (m), (NCH) 2789 (s).

EXAMPLE 4 Preparation of(R)-(1′-benzyl-3-bromo-[1,3′]bipyrrolidinyl-2-one)

A solution of 5.0 g of (R)-1-(phenylmethyl)-3-pyrrolidinamine in 50.0 mlCH₃CN was treated at rt with 2.72 g of Na₃PO₄. The resulting fine lightyellow suspension was cooled to 0° C. and treated with a solution of10.07 g of 2,4-dibromobutyrylbromide (prepared according to Marinelli,E. R.; Arunachalam, T.; Diamantidis, G.; Emswiler, J.; Fan, H.; Neubeck,R.; Pillai, K. M. R.; Wagler, T. R.; Chen, C.-K.; et al. Tetrahedron(1996), 52(34), 11177-11214) in 5.0 ml of CH₃CN over 20 min. After 30min the very fine suspension was filtered and concentrated to a volumeof 30 ml, and then treated with 130.1 ml of 0.497 M NaOH solution atroom temperature. The resultant turbid orange solution was stirred for 2h, concentrated and the resultant aqueous phase extracted with threeportions of 50 ml of TBME. The combined organic phases were washed withH₂O until neutral, dried over MgSO₄ and concentrated to give 5.79 g(63%) of (R)-(1′-benzyl-3-bromo-[1,3′]bipyrrolidinyl-2-one) as yellowwaxy crystals.

The fine suspension from above was triturated with 100 ml CH₃CN,filtered, concentrated to a volume of 40 ml and treated with 50 ml of0.497 m NaOH, then stirred at rt for 1 h. The CH₃CN was distilled awayand the resultant aqueous phase worked up as above to give a further2.57 g (28%) of product. The total yield 8.36 g (91%). ¹H-NMR (CDCl₃,400 MHz, 14:1 mixture of diastereomers) 7.32 (m, 5H, H-ar), 4.65 (m, 1H,NCH), 4.39 (dd, 1H, CHBr), 3.60 (2d, 2H, PhCH₂N), 3.52 (m, 2H, CONCH₂),2.92 (ddd, 1H, PhCH₂NCH ₂CH₂), 2.71 (dd, 1H, PhCH₂NCH ₂CHNCO), 2.49 (m,2H, COCHBrCH ₂ and PhCH₂NCH ₂CH), 2.25 (m, 3H, PhCH₂NCH₂CH ₂, COCHBrCH ₂and PhCH₂NCH ₂CH₂), 1.70 (m, 1H, PhCH₂NCH₂CH ₂).

EXAMPLE 5 Preparation of(R)-(1′-benzyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenyl-phosphonium;bromide

A suspension of 800 mg of 1′-benzyl-3-bromo-[1,3′]bipyrrolidinyl-2-onein 1.0 ml toluene was treated with 1.95 g of Ph₃P and stirred at 110° C.for 30 min whereupon TLC indicated the reaction was complete. The browntwo phase mixture was diluted with 10 ml EtOAc and the organic phase wasextracted with three portions of 10 ml of saturated NaBr solution. Thecombined aqueous phases were washed three times with 10 ml EtOAc (toremove Ph₃P), and then extracted seven times with 15 ml CH₂Cl₂, thecombined organic phases dried over MgSO₄ and concentrated to give 1.13 g(78%) of(R)-(1′-benzyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenyl-phosphoniumbromide as a light brown foam. ¹H-NMR (250 MHz; CDCl₃, ˜1:1 mixture ofdiastereomers): 7.32-8.04 (m, 5H), 7.50-7.82 (m, 10H), 7.19-7.40 (m,5H), 6.44-6.64 (m, 1H), 4.39-4.50 (m, 1H), 3.10-3.88 (m, 5H), 2.85-3.00(m, 0.5H), 2.62-2.80 (m, 1H), 2.32-2.5 (m, 0.5 H), 1.72-2.32 (m, 5H).

EXAMPLE 6 Preparation of(1′-tert-butoxycarbonyl-2-oxo-[1,3′]-(R)-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium;bromide

A solution of the mixture of 880 mg of(R)-(1′-benzyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenyl-phosphoniumbromide and 820 mg of di-tert.-butyl-dicarbonate (commercially availablefrom Fluka) in 5.5 ml MeOH was treated with 880 mg of 10% Pd/C(commercially available from Degussa; 1835) and hydrogenated at 60° C.for 3 d and then filtered and evaporated to give 627 mg (70%) of(1′-tert-butoxycarbonyl-2-oxo-[1,3′]-(R)-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium;bromide as a beige foam. ¹H-NMR (CDCl₃, 250 MHz; mixture ofdiastereomers and rotamers): 7.82-8.01 (m, 5H), 7.55-7.81 (m, 10H),6.71-6.88 (m, 1H), 4.22-4.51 (m, 1H), 3.70-3.91 (m, 1H), 3.35-3.50 (m,1H), 2.61-3.32 (m, 4H), 1.90-2.20 (m, 2H), 1.64-1.80 (m, 2H), 1.44 (s,9H).

1. A process for the preparation of bipyrrolidinyl compounds of formula I

wherein * signifies an asymmetric center with an (R) or (S) configuration and X represents chlorine, bromine or iodine; comprising: step 1) coupling the compound of formula II

wherein * is as defined above with a compound of formula X(CH₂)₂CH(X)COX wherein X is independently of each other chlorine, bromine or iodine; and subsequent cyclizing the compound of formula II in the presence of a base to obtain a compound of formula III

wherein * and X are as defined above; step 2) reacting the compound of formula III with triphenylphosphine to obtain the phosphonium salt of formula IV

wherein * and X are as defined above; and step 3) reacting the phosphonium salt of formula IV with di-tert.-butyl-dicarbonate under hydrogenation conditions to obtain the compounds of formula I.
 2. A process as claimed in claim 1 wherein step 1 is carried out in the presence of Na₃PO₄ and the subsequent cyclization reaction is carried out in the presence of sodium hydroxide.
 3. A process for the preparation of bipyrrolidinyl compounds of formula I according to claim 1 wherein compound of formula II

wherein * is as defined above is prepared by reaction of the compound of formula VII

wherein * is as defined above with a base; and the subsequent reduction reaction is carried out with a reducing agent to obtain the amino pyrrolidine compound of formula II.
 4. A process for the preparation of bipyrrolidinyl compounds of formula I according to claim 3 wherein the compound of formula VII

wherein * is as defined above is prepared by removal of the amino protecting group of compounds of formula VI

wherein * is as defined above and R² is an amino protecting group in the presence of an acid to obtain the amino salt of compound of formula VII.
 5. A process for the preparation of bipyrrolidinyl compounds of formula I according to claim 4 wherein compounds of formula VI

wherein * and R² are as defined above is prepared by cyclization reaction of compounds of formula V

wherein R¹ is an alkyl group and * and R² are as defined above in the presence of a base; and subsequent reaction with benzyl bromide to obtain a compound of formula VI.
 6. A process as claimed in claim 1, wherein step 2 is carried out in an aromatic solvent.
 7. A process as claimed in claim 1, wherein step 3 is carried out in methanol and the hydrogenation is carried out in the presence of palladium on activated carbon.
 8. A process as claimed in claim 1, wherein * signifies an asymmetric center with (R) configuration and R¹ is methyl or ethyl, R² is benzyloxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl and X is chlorine or bromine.
 9. A process as claimed in claim 1, wherein R¹ is methyl, R² is benzyloxycarbonyl and X is bromine. 